DNA Unwinding by ASCC3 Helicase is Coupled to ALKBH3-dependent DNA Alkylation Repair and Cancer Cell Proliferation

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Nov 8

PMID 22055184

Citations 109

Authors

Sebastian Dango

Nima Mosammaparast

Mathew E Sowa

Li-Jun Xiong

Feizhen Wu

Keyjung Park

Mark Rubin

Steve Gygi

J Wade Harper

Yang Shi

Affiliations

Soon will be listed here.

Abstract

Demethylation by the AlkB dioxygenases represents an important mechanism for repair of N-alkylated nucleotides. However, little is known about their functions in mammalian cells. We report the purification of the ALKBH3 complex and demonstrate its association with the activating signal cointegrator complex (ASCC). ALKBH3 is overexpressed in various cancers, and both ALKBH3 and ASCC are important for alkylation damage resistance in these tumor cell lines. ASCC3, the largest subunit of ASCC, encodes a 3'-5' DNA helicase, whose activity is crucial for the generation of single-stranded DNA upon which ALKBH3 preferentially functions for dealkylation. In cell lines that are dependent on ALKBH3 and ASCC3 for alkylation damage resistance, loss of ALKBH3 or ASCC3 leads to increased 3-methylcytosine and reduced cell proliferation, which correlates with pH2A.X and 53BP1 foci formation. Our data provide a molecular mechanism by which ALKBH3 collaborates with ASCC to maintain genomic integrity in a cell-type specific manner.

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